European Journal of Pediatrics (2023) 182:1601–1609

https://doi.org/10.1007/s00431-023-04825-4

RESEARCH

Incidental hypertransaminasemia in children—a stepwise approach

in primary care
Joana Meneses Costa1 · Sara Martins Pinto2 · Ermelinda Santos‑Silva3,4,5 · Helena Moreira‑Silva3

Received: 10 October 2022 / Revised: 10 January 2023 / Accepted: 15 January 2023 / Published online: 26 January 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023

Abstract
Children with elevated liver enzymes are occasionally discovered through laboratory work-up from different clinical sce-
narios. Although the majority will have transient and/or benign conditions, a subgroup will have underlying liver disorders.
The differential diagnosis is broad and therefore, a systematic approach is of utmost importance. In this article, we reviewed
the most recent and relevant literature to provide a comprehensive overview of the main disease processes that cause hyper-
transaminasemia in children. Ultimately, we propose a practical stepwise approach to guide primary care physicians in the
evaluation of abnormal liver enzymes in asymptomatic children. The first step is to obtain a complete history along with a
thorough physical examination to exclude red flags, which should dictate urgent consultation with a paediatric gastroenter-
ologist or hepatologist.
  Conclusion: Hypertransaminasemia is a challenging scenario in the primary care setting. The aetiology can be broad,
ranging from hepatic and extrahepatic to transient versus chronic liver disease. Timely referral to a specialised centre is of
paramount importance for conducting targeted research and to not miss the chance of identifying a progressive, but still
asymptomatic, treatable liver disease.

What is Known:
• Elevated liver enzyme is a challenging scenario in the primary care setting.
• There are few studies guiding the evaluation of asymptomatic hypertransaminasemia in the paediatric population and a standardised
approach is lacking.
What is New:
• We propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes.

Keywords  Elevated liver enzymes · Hypertransaminasemia · Children · Primary care

Abbreviations
Communicated by Peter de Winter. A1AT Alpha1-antitrypsin
AIH Autoimmune hepatitis
* Helena Moreira‑Silva
hel.m.silva@hotmail.com ASC Autoimmune sclerosing cholangitis
ALD Autoimmune liver disease
1
Valbom Family Health Unit, Group of Health Centers ALP Alkaline phosphatase
of Gondomar, Porto, Portugal
ALT Alanine aminotransferase
2
Nascente Family Health Unit, Group of Health Centers AST Aspartate aminotransferase
of Gondomar, Porto, Portugal
CD Celiac disease
3
Pediatrics Division, Gastroenterology Unit, Centro Hospitalar COVID-19 Coronavirus disease-19
Universitário do Porto, Centro Materno Infantil do Norte,
CF Cystic fibrosis
Largo da Maternidade No 45. 4050‑651, Porto, Portugal
4
CK Creatine kinase
Integrated Master in Medicine, Instituto de Ciências
GGT​ G-glutamyl transferase
Biomédicas Abel Salazar, Universidade do Porto, Porto,
Portugal DILI Drug-induced liver injury
5 HAV Hepatitis A
REQUIMTE, Laboratory of Biochemistry, Department
of Biological Sciences, Faculdade de Farmácia, UCIBIO, HCV Hepatitis C
Universidade do Porto, Porto, Portugal HBV Hepatitis B

13
Vol.:(0123456789)
1602
IBD Inflammatory bowel disease
IEM Inborn errors of metabolism
NAFL Nonalcoholic fatty liver
NAFLD Non-alcoholic fatty liver disease
NASH Non-alcoholic steatohepatitis
WD Wilson disease
Introduction
Primary care physicians are increasingly faced with elevated
liver enzymes found in a laboratory work-up from different
scenarios, both in symptomatic and asymptomatic patients
[1–5]. Although the majority will have benign conditions,
a subgroup will have underlying liver disorders that will
require appropriate investigations. In adults, the causes
of elevated liver enzymes, other than viral hepatitis and
obesity-related liver disease, are more liver-specific and its
evaluation is well-stablished in the literature [6, 7]. In the
paediatric population, liver diseases gather a large spectrum
of diagnoses, from hepatic and non-hepatic aetiologies to
multisystemic disorders, making them a challenge for pri-
mary care physicians [1].
Several studies report that the prevalence of abnormal liver
enzymes varies according to the country, type of food, sanita-
tion conditions, time of the year, and the quality of healthcare
[3]. It is estimated that between 3.5 and 12.4% of asympto-
matic adolescents have elevated liver enzymes [3, 8–10]. The
most common cause in underdeveloped countries is infection,
mainly caused by hepatitis A virus (HAV) [3]. On the other
hand, in developed countries, non-alcoholic fatty liver disease
(NAFLD) is the leading cause, although hepatobiliary, genetic,
and autoimmune disorders are important contributors [6, 11].
However, the prevalence and aetiology of hypertransamina-
semia in European children from all age groups are not well-
known, probably because the condition is underestimated [4].
In addition, there are few studies guiding the evaluation of the
asymptomatic hypertransaminasemia in the paediatric popula-
tion and a standardised approach in the primary care setting
is lacking.
The aim of this article is to provide a comprehensive
overview of the basic disease processes that cause hyper-
transaminasemia in children. Then, we developed a stepwise
algorithm to guide primary care physicians in the evalua-
tion of abnormal liver enzymes in asymptomatic children.
The first step is to obtain a complete history and perform a
thorough physical examination in an effort to exclude the
presence of red flags [12]. In these cases, timely referral to
a specialised centre is of paramount importance so as not to
miss the chance of identifying progressive, but still asymp-
tomatic, treatable liver disease [4, 6].
13
European Journal of Pediatrics (2023) 182:1601–1609
Keywords in paediatric hepatology
Markers of cytolysis: aspartate aminotransferase
(AST) and alanine aminotransferase (ALT)
Aminotransferases (transaminases) are intracellular enzymes
found in various tissues at different proportions and nor-
mally found in the plasma in low levels [3]. AST is found,
in decreasing order of concentration, in the liver, heart, skel-
etal muscle, kidneys, brain, pancreas, lungs, leukocytes, and
erythrocytes, and its half-life in circulation is about 17 − 18 h
[1, 5, 7, 13, 14]. ALT is found in low concentrations in other
tissues beyond the liver, making this enzyme more spe-
cific of liver injury. Its half-life is longer than that of AST
(45 − 47 h) [1, 5, 13]. In clinical settings, their elevation
occurs due to the enzyme leakage following cell damage
or change in cell membrane permeability [15] in those tis-
sues. Thus, the aetiology can be broad, ranging from hepatic
and extrahepatic to transient versus chronic liver disease.
Additionally, the degree of AST and ALT elevation does not
always correlate with the degree of hepatocellular damage
[3, 6, 7, 16].
Markers of cholestasis: bilirubin, bile acids, alkaline
phosphatase (ALP), and g‑glutamyl transferase (GGT)
Unconjugated bilirubin is a heme degradation product trans-
ported to the liver and conjugated by the UDP-glucuronyl
transferase into a water-soluble form—conjugated/direct
bilirubin—secreted across the canalicular membrane into the
bile [14]. Increase in conjugated bilirubin is due to decreased
excretion into the bile and leakage from the hepatocytes into
the serum and may result from impairment of the hepato-
cyte’s canalicular membrane, damage to the canaliculi, and/
or obstruction of extrahepatic bile ducts [17].
ALP is an enzyme that is responsible for transportation of
metabolites across the cell membrane. Under normal condi-
tions, it is predominantly of liver and bone origin. Elevation
of ALP levels can be present in several hepatic and non-
hepatic processes. In hepatobiliary diseases, ALP elevation
results from increased de novo synthesis in the liver followed
by release into the circulation. Retained bile acids appear to
play a central role in this process [14].
Gamma glutamyl-transferase (GGT) is located on the
membrane of cells with high secretory or absorptive activi-
ties, being more abundant in the liver, kidney, pancreas, intes-
tine, and prostate, but not in bone. Its activity can be useful
to determine whether an elevation of alkaline phosphatase is
of liver or bone origin. High ALP levels in conjunction with
elevated GGT point to cholestatic disorders with hepatobil-
iary injury (e.g. primary sclerosing cholangitis) [14].
European Journal of Pediatrics (2023) 182:1601–1609
Liver function tests
The liver synthesises both albumin and many of the blood
coagulation factors required to produce a normal prothrombin
time. Thus, serum albumin and prothrombin time are essential
tests when assessing liver function, although not liver-specific.
The half-life of serum albumin is around 19 to 21 days,
whereas the half-life of blood coagulation factor may be less
than 1 day, so these tests, along with physical examination
findings, can be used to assess both acute and chronic liver
dysfunctions [14].
The liver plays a fundamental role in the detoxification
of the human body, and ammonia, the final product of the
urea cycle, is the utmost illustrative metabolite of this role.
Increased serum ammonia levels may result from substrate
overload and/or decreased ability to metabolise and elimi-
nate, and they are usually associated with variable degrees
of encephalopathy [18].
Transaminase reference values
In common practice, reference ranges are defined as the
mean value within ± 2 standard deviations obtained in
healthy individuals [5, 6]. By definition, we should con-
sider hypertransaminasemia as an elevation of liver enzymes
greater than 1.5 to 2 times the upper limit or higher than the
97th percentile, which is a difficult definition to apply in
the paediatric population [13], mainly because of the high
variability of ALT and AST with age, sex, weight, time of
day, and level of exercise [2, 5, 19]. For an ALT reference
range, England et al. [20] proposed ALT centiles stratified
by sex and age in a healthy European population as shown in
Table 1. AST and GGT also reveal sex-specific differences
and age-dependent fluctuations [21, 22].
The magnitude of aminotransferase alterations can be
classified as ‘mild’ (2 − 5 times the upper reference limit),
‘moderate’ (5 − 10 times the upper reference limit), or
‘marked or severe’ (> 10 times the upper reference limit) [5,
6, 13]. Mild or moderate hypertransaminasemia is often seen
with chronic liver disease (e.g. chronic viral hepatitis, non-
alcoholic steatohepatitis), although transient elevations may
also be seen in children with mild hepatic insults [13]. For
patients with severe elevations of serum aminotransferases,
markers of liver failure should be promptly excluded.
Table 1  Upper limit of normal of ALT serum levels (IU/L) stratified
by sex and age [20–22]
0–18 months  > 18 months 12–17 years
Boys 60 40 25.8
Girls 55 35 22.1
1603
Understanding the scope of elevated
liver enzymes
Elevated liver enzymes are often a challenging scenario in com-
mon clinical practise. Although a normal physiological phe-
nomenon in certain instances, it may also reflect liver disease.
The differential diagnosis is broad; however, it is not intended
that primary care providers pursue extensive evaluations and
work-up. We believe that primary care providers should be
aware of the main disease processes affecting each age group,
as they have a pivotal role in the referral of these patients for
further assessment and management. Conversely, missing the
referral of mild or moderate liver enzyme elevations could
mean missing a progressive, yet treatable, condition.
To guide primary care clinicians in the interpretation
of elevated liver enzymes in asymptomatic children, we
can divide the main causes into hepatic and extrahepatic
(Table 2) and consider the most prevalent diseases in each
age group (Fig. 1) to help with the selection of the most
appropriate complementary tests.
Causes of hepatic origin
(I) Non-alcoholic fatty liver disease
NAFLD has emerged as the most common cause of
hypertransaminasemia in children and adolescents in devel-
oped countries with a prevalence that rounds 2.6 − 9.8%
[23]. The increased burden of NAFLD is strongly related to
the increase in fructose consumption, overweight/obesity,
and metabolic syndrome [23–26]. It usually affects children
older than 10 years and rarely appears under 3 years. In this
age group, NAFLD should alert for secondary causes, such
as endocrine disorders or inborn errors of metabolism.
Table 2  Main causes of hypertransaminasemia in asymptomatic chil-
dren
Hepatic origin Extrahepatic origin
NAFLD/NASH Myopathies/muscular dystrophies
Viral infections Strenuous physical exercise
Alpha-1-antitrypsin deficiency Muscular lesion induced by drugs
Autoimmune liver disease Myocardiopathies
Wilson’s disease Nephropathies
DILI Haemolytic disorders
Celiac disease Macro-AST
Inflammatory bowel disease
Cystic fibrosis
Shwachman-Diamond syndrome
Inborn errors of metabolism
NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steato-
hepatitis, DILI drug-induced liver injury
13
1604
NASPGHAN guidelines define the screening for NAFLD
in obese children (BMI ≥ 95 percentile) between 9 and
11 years old or overweight children (95 < BMI ≥ 85 percen-
tile) with risk factors such as hypertension, hyperinsuline-
mia, hypertriglyceridemia, hyperuricemia, and dyslipidae-
mia [26].
NAFLD represents a spectrum of fatty liver disease,
encompassing three categories, defined by histologic find-
ings: non-alcoholic fatty liver (NAFL), non-alcoholic steato-
hepatitis (NASH), and NASH cirrhosis. The utility of histol-
ogy for routine clinical assessment of NAFLD is limited by
its invasive nature. Thus, in clinical practice the diagnosis
relies on either evidence of hepatic steatosis from imaging
(mostly ultrasound) and/or elevations in serum aminotrans-
ferase levels, especially ALT [24, 26–28].
(II) Viral infections
Hepatitis caused by viral infection due hepatotropic
virus such as A, B, C, E, and non-A-E virus, as well as
other viral systemic febrile infections, is a common cause
of hypertransaminasemia. In developing countries, infec-
tions are one of the main causes of abnormal transami-
nases levels, especially hepatitis A (HAV). Consequently,
ethno-geographic origin and other risk factors for infection
should be carefully assessed, such as vaccination status,
history of blood product transfusion, sexual behaviour, tat-
tooing, or ingestion of potentially contaminated food [3, 6,
23, 24, 29].
HAV is usually an acute and self-limited condition; ful-
minant hepatic failure occurs in fewer than 1 percent of
cases [29, 30]. HAV infection is preventable via vaccina-
tion, but outbreaks still occur in countries with high ende-
micity such us Middle East and Northern African region.
AST, ALT, GGT, and bilirubin rise as the infection starts
and ALT rapidly increases before symptoms emerge. After
that, ALT gradually decreases and normalises when jaundice
disappears. However, in paediatric patients, HAV may be
Fig. 1  Most frequent causes of
hypertransaminasemia by age
group. DILI drug-induced liver
injury, NAFLD non-alcoholic
fatty liver disease, IBD inflam- Metabolic Disorders
matory bowel disease Immunodeficiency
Liver masses
Biliary malformaon
Cysc fibrosis
Infant/toddler
13
European Journal of Pediatrics (2023) 182:1601–1609
followed by up to 1 year of intermittent hypertransamina-
semia due to relapsing viremia [6, 29, 30].
Most patients with chronic viral hepatitis have minimal
elevations in ALT/AST levels, with a ratio of approxi-
mately 1 [17]. Hepatitis B (HBV) vaccination largely
reduced the infection in children and mother-to-infant
transmission; however, travel and immigration main-
tain an ample reservoir of HBV. Concerning hepatitis C
(HCV), although less infectious than HBV, it remains a
global issue in the absence of an effective vaccine [6]. In
addition, paediatric HCV carriers may have fluctuating
transaminase levels even in the presence of serious liver
damage [6, 29, 30].
Other viral infections caused by hepatotropic non-A-E
virus, such as Epstein-Barr, cytomegalovirus, adenovirus,
coxsackievirus, enterovirus, herpes simplex, and rubella,
should be considered in the appropriate clinical setting.
Similarly, non-viral infections (bacteria or parasites) could
also be the responsible agent [29, 31–33].
Coronavirus disease-19 (COVID-19) is the latest global
pandemic caused by SARS-CoV-2 (severe acute respira-
tory syndrome). Although it predominantly causes respira-
tory symptoms, liver damage is among the main extrapul-
monary manifestations. It typically leads to a temporary
slight to moderate elevation of liver enzymes without sig-
nificant hepatic synthetic function impairment [34, 35].
The mechanism of liver injury is related to the high ACE2
expression in cholangiocytes and hepatocytes, supporting
the hypothesis of virus-related hepatic damage [36].
(III) Drug-induced liver injury (DILI)
DILI is an important but often unrecognised cause of
hypertransaminasemia in children. Most are subclinical with
only laboratory abnormalities but can progress to a symp-
tomatic or even a fulminant hepatitis [37]. Acetaminophen
hepatotoxicity is a paradigmatic and well-documented
example of predictable, dose-dependent injury; however, the
Viral infecons NAFLD
Celiac disease IBD
DILI Autoimmune liver disease
Alpha-1-antrypsin Wilson disease
Young child/adolescent
European Journal of Pediatrics (2023) 182:1601–1609
majority of drugs causing DILI have idiosyncratic hepatotox-
icity with variable latency periods, even in individuals with
a long and previously uneventful exposure [37]. Antimicro-
bials (amoxicillin, amoxicillin-clavulanic, minocycline) and
drugs acting on the central nervous system (antiepileptics,
antidepressants, attention deficit hyperactivity disorder medi-
cations) represent most paediatric DILI cases. However, over-
the-counter medications, herbal medicines, or even illicit
drugs or substance abuse should be considered, especially in
adolescents. Additionally, several drugs (e.g. minocycline,
lamotrigine, azithromycin, or amoxicillin) can induce an idi-
osyncratic reaction with an immune-allergic component that
resembles an autoimmune hepatitis. Thus, DILI diagnosis
requires a high index of suspicion and a methodical exclusion
of other paediatric liver diseases [3, 21, 26].
(IV) Alpha1-antitrypsin deficiency
Alpha1 antitrypsin deficiency is an autosomal codomi-
nant disease that predisposes to lung and liver damage.
Liver disease predominates in children but has a variable
presentation depending on the disease phenotype. It may
manifest with neonatal cholestasis in those with severe
deficiency (e.g. PI ZZ phenotype) or with elevated liver
enzymes in infancy and early childhood or cirrhosis with
hepatosplenomegaly in the adolescent or young adult
[38–40].
Screening tests involve detecting low levels of serum
alpha-1 antitrypsin (A1AT). This measurement should be
accompanied by an assessment of C-reactive protein, since
A1AT is an acute-phase reactant protein that increases
during infection or inflammation [41]. Phenotype deter-
mination is necessary to confirm the diagnosis [17]. Nev-
ertheless, these patients should be referred to a tertiary
paediatric centre for evaluation and follow-up.
(V) Autoimmune liver disease (ALD)
ALD is a chronic progressive inflammatory liver dis-
ease that encompasses autoimmune hepatitis (AIH) and
autoimmune sclerosing cholangitis (ASC). It is character-
ised by elevated transaminases and/or GGT levels, hyper-
gammaglobulinemia, presence of specific autoantibodies,
and a distinctive histology [6, 42].
ALD often shows a female to male predominance and is
frequently associated with a family or personal history of con-
comitant autoimmune disorders [43]. It can present acutely
with a clinical picture of hepatitis, or insidiously with a fluc-
tuating course, either asymptomatically or with unspecific
symptoms (fatigue, nausea, abdominal pain) [6, 42, 44]. Inci-
dental elevation of transaminases or a cholestatic biochemi-
cal profile can be the only presenting feature. Establishing a
1605
definitive diagnosis is sometimes complex and cumbersome,
and referral to a tertiary centre is recommended.
(VI) Wilson disease (WD)
WD is an inherited autosomal recessive disorder of cop-
per metabolism, involving a defect in ATP7B, resulting in
impaired biliary copper excretion, leading to its accumula-
tion, particularly in the liver and brain [45]. In childhood,
WD has a predominant hepatic phenotype with an average
age at presentation of 12 years [6, 46]. Liver disease may
be completely asymptomatic, presenting with only mildly
increased transaminases. Initial evaluation or screening
includes testing for serum ceruloplasmin levels (reduced in
most patients with WD) and 24-h urinary copper excretion.
Definitive diagnosis requires liver biopsy and/or genetic
tests [6, 46, 47]. Prompt treatment with copper-chelating
agents and/or zinc hampers hepatic damage and/or pre-
vents development of further neurological deterioration
[6, 46, 48].
Elevated liver enzymes in multisystemic disorders
(I) Celiac disease (CD)
CD is a systemic autoimmune disease due to dys-
regulated intestinal mucosal immune response in geneti-
cally susceptible individuals exposed to dietary gluten.
Although it mainly affects the gut, many extraintestinal
manifestations can arise. The liver involvement in CD is
characterised by a mild to moderate increase of transami-
nases, often correlated to duodenal mucosal damage [49].
Normalisation of liver enzymes usually occurs within
12–24 months of a strict gluten-free diet and follows the
decline in serum levels of anti-tissue transglutaminase
[50–52]. In the case of persistent hypertransaminasemia,
other possible causes of liver disease should be consid-
ered, mainly ALD [6, 52].
(II) Inflammatory bowel disease (IBD)
IBD patients may present with elevated liver enzymes
resulting from the disease process itself, or the result of
an underlying primary hepatic disorder such as ALD.
Although less common, medication toxicity can also
induce liver injury. The relation between IBD extent or
duration and elevated liver enzymes is controversial; nev-
ertheless, in the absence of concomitant disorders, low-
grade elevations are usually transient [53–55].
(III) Cystic fibrosis (CF)
13
1606
CF is a progressive and multisystemic disease result-
ing from mutations in the cystic fibrosis transmembrane
conductance receptor, expressed at the apical membrane
of epithelial cells. Therefore, hepatobiliary disease in CF
is the result of inspissated bile, causing ductular obstruc-
tion and hepatotoxicity. Although hepatic involvement is
common, CF rarely has an exclusive hepatic presentation
[56–60].
(IV) Inborn errors of metabolism (IEM)
Newborn screening programs with tandem mass spec-
trometry are used in neonatal screening for several IEM
[11] largely identified in the neonatal period. However,
many patients will only present later in infancy or child-
hood, with a wide range of manifestations, and elevated
liver enzymes can be the presenting sign. Although indi-
vidually rare, IEM collectively account for 20 − 30% of
liver disease in infancy and childhood [4, 61]. Important
indicators of an IEM are consanguinity, previous miscar-
riages, dysmorphic features, developmental delay, and
hepato(spleno)megaly. The diagnostic approach is cum-
bersome; thus, a high index of suspicion and discussion
with a metabolic specialist centre is the key to diagnosis
[4, 61, 62].
Main causes of elevated liver enzymes
of non‑hepatic origin
Elevated transaminases can signify extra-hepatic disor-
ders, most commonly muscle diseases and haemolysis
[7]. In the case of muscle disease, elevation of ALT and
AST is accompanied by elevation in creatine kinase (CK),
signalling muscle breakdown. Thus, CK is an easy and
inexpensive marker that can be used as a screening process
for muscular dystrophies in children with isolated ALT/
AST elevation, in the presence of normal bilirubin and
GGT serum levels [63]. CK elevation can also be caused
by cellular necrosis induced by drugs or toxins and strenu-
ous exercise [6, 64, 65].
Haemolysis can also be a cause of hypertransaminasemia,
along with elevated unconjugated bilirubin, haptoglobin lev-
els, and reticulocyte count.
Isolated elevation of AST in the presence of normal
laboratory work-up suggests a diagnosis of macro-aspartate
aminotransferase (macro-AST). Macro-AST complexes are
formed from self-polymerization or binding to immuno-
globulins, leading to decreased renal clearance and a false-
positive elevation of AST [66]. The diagnosis of macro-AST
is using polyethylene glycol (PEG) precipitation.
13
European Journal of Pediatrics (2023) 182:1601–1609
Diagnostic work‑up
Investigating hypertransaminasemia is fundamental to
diagnose treatable liver conditions and to institute spe-
cific treatment in a timely manner [6, 13, 16]. The pro-
posed algorithm was designed to guide the approach in
primary care facilities, highlighting some diagnostic
considerations:
(a) Exclude the presence of red flags, namely pallor, jaun-
dice, hepatomegaly + / − splenomegaly, clinical signs
of chronic liver disease (telangiectasias, abdominal col-
lateral circulation, palmar erythema, digital clubbing),
clinical or biochemical evidence of liver failure, and
personal or family history of liver disease or autoim-
mune disease.
(b) Discriminate between mild and moderate/severe liver
enzyme elevation and manage accordingly:
– Mild liver enzyme elevation should be re-assessed
in 1–2 weeks. In the retesting panel, we should not
only include ALT and AST, but also CK, LDH, and
complete blood count to ensure that the enzymes are
of liver origin, differentiating hepatic from extra-
hepatic causes; GGT, bilirubin, albumin, total pro-
teins, and coagulation tests are also valuable tests to
guide subsequent management (Fig. 2)
– Expedite referral of patients with evidence of liver
dysfunction (high bilirubin, low albumin, and pro-
longed PT or INR)
– Moderate or marked hypertransaminasemia in the
context of a clear infectious aetiology must be
re-assessed in 48–72 h. In the case of suspected
drug-induced liver injury and in the absence of
liver failure, the first step should be to stop any
presumptive offenders (if possible) and re-eval-
uate the patient in the following days. Referral
should be considered when either the medication
cannot be stopped or no improvement is seen after
a week. Patients with the possibility of delayed
drug-induced hepatotoxicity and those with other-
wise undefined circumstances should be referred.
(c) We suggest concluding the follow-up of an asympto-
matic patient with normal physical examination and
normal values of liver function tests in the presence of
two consecutive normal tests 1 month apart.
(d) Articulation with a tertiary centre may be needed in all
steps and consultation with a specialist is recommended
in questionable cases.
European Journal of Pediatrics (2023) 182:1601–1609 1607

Hypertransaminasemia Red Flags?

Poor weight gain, hypotonia, delayed psychomotor development, pallor, jaundice, hepatomegaly +/-
splenomegaly, clinical signs of chronic liver disease (telangiectasias, abdominal collateral circulaon, Yes Urgent Referral
Clinical history + physical examina‰on palmar erythema, digital clubbing), clinical or biochemical evidence of liver failure, family history of liver
disease or autoimmune disease.

No

Moderate/Severe
Mild Hypertransaminasemia Hypertransaminasemia

1-2 weeks

Retesng panel: AST, ALT, GGT, CK, LDH, total proteins, albumin, Viral Drugs? Illicit
Unknown
bilirubin, complete blood count and coagulaon; infec‰on? substances?*
48-72hours
Consider abdominal ultrasonography.

Stop the Urgent

possible Referral
↑ AST, ↑ ALT offenders *
Normal

Re-evaluate in
Coagulopathy Normal GGT / ↑ ↑ total CK ↑ LDH, Indirect 48-72hours
↓ albumin Bilirubin Fluctuang levels ?
↑ Total proteins
Overweight? Physical exercise?
Repeat in 1 week Consider hematological
cause Repeat in 3
Urgent Referral
months
No Yes Normal ↑
Hospital Referral
Weight loss and ↑ Normal
retesng in 3-6 months Surveillance
Surveillance
↑ Normal

Hospital Referral

Fig. 2  Proposed management algorithm to guide the approach in primary care facilities. *Referral should be considered when either the medica-
tion cannot be stopped or no improvement is seen in the following days

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articulation with a tertiary centre is a valuable tool for con- a guide for clinicians. CMAJ 172(3):367–379
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Authors’ contributions  Joana Meneses Costa and Sara Martins Pinto: 8. Fraser A, Longnecker MP, Lawlor DA (2007) Prevalence of elevated
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